Unsaturated acetylene phosphonate derivatives of purines

Disclosed are novel unsaturated acetylene phosphonate derivatives of certain purines or pyrimidines useful as antiviral agents, methods useful for their preparation and use of these compounds as antiviral agents effective against DNA viruses, retroviruses and viruses involved in tumor formation.

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Claims

1. A compound of the formula: ##STR24## the stereoisomeric forms and mixtures thereof, tautomeric forms or the pharmaceutically acceptable salts thereof, wherein

X.sub.1 is H or NH.sub.2;
X.sub.2 is OH or NH.sub.2;
Z is nothing, CH.sub.2, CH.sub.2 CH.sub.2, or CH.sub.2 O;
W is ##STR25## wherein T is nothing, T' or T", wherein
T' is CH.sub.2 CH.sub.2, and
T" is CH.sub.2 OCH.sub.2, CH.sub.2 OCH(CH.sub.2 OH);
R.sub.3 and R.sub.4 are each independently OH, OR.sub.5, OR.sub.5 ', or --O--CH(R.sub.6)--O--C(O)R.sub.5, provided that when one of R.sub.3 and R.sub.4 is OH the other is not --O--CH(R.sub.6)--O--C(O)R.sub.5, wherein R.sub.5 and R.sub.5 ' are each independently C.sub.1-15 alkyl or benzyl, and R.sub.6 is H or C.sub.1-10 alkyl.

2. The compound according to claim 1 wherein

when W=W.sub.d and T=T" then Z is CH.sub.2.

3. The compound according to claim 1 wherein T is T" and T" is CH.sub.2 OCH.sub.2.

4. The compound according to claim 1 wherein Z is CH.sub.2 or CH.sub.2 O.

5. The compound according to claim 1 wherein the compound is 9-(4-dihydroxyphosphorylmethoxy-2-butynyl)guanine.

6. The compound according to claim 1 wherein X.sub.1 is NH.sub.2 and X.sub.2 is OH.

7. A pharmaceutical composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable carrier.

8. A method of treating a patient for a viral infection of DNA viruses, retroviruses or viruses involved in tumor formation by administration to a patient of a sufficient amount of the compound according to claim.

9. A method of preparing a compound of the formula: ##STR26## the stereoisomeric forms and mixtures thereof, tautomeric forms or the pharmaceutically acceptable salts thereof, wherein

X.sub.1 is H or NH.sub.2;
X.sub.2 is OH or NH.sub.2;
Z is nothing, CH.sub.2, CH.sub.2 CH.sub.2, or CH.sub.2 O;
W is ##STR27## wherein T is nothing, T' or T", wherein
T' is CH.sub.2 CH.sub.2, and
T" is CH.sub.2 OCH.sub.2, CH.sub.2 OCH(CH.sub.2 OH
R.sub.3 and R.sub.4 are each independently OH, OR.sub.5, OR.sub.5 ', or --O--CH(R.sub.6)--O--C(O)R.sub.5, provided that when one of R3 or R4 is OH the other is not --O--CH(R.sub.6)--O--C(O)R.sub.5, wherein R.sub.5 and R.sub.5 ' are each independently C.sub.1-15 alkyl or benzyl, and R.sub.6 is H or C.sub.1-10 alkyl
and is optionally hydrolyzed to provide the compound wherein R.sub.3 and R.sub.4 are each --OH.
Referenced Cited
U.S. Patent Documents
5032592 July 16, 1991 Hughes et al.
5055458 October 8, 1991 Bailey et al.
5166198 November 24, 1992 Harnden et al.
5532225 July 2, 1996 Reist et al.
Foreign Patent Documents
0173624 March 1986 EPX
0253412 January 1988 EPX
0353955 February 1990 EPX
0481214 April 1992 EPX
0532423 March 1993 EPX
9201698 February 1992 WOX
9209611 June 1992 WOX
9307157 April 1993 WOX
Other references
  • J. Org. Chem (1992) vol. 57, No. 8, pp. 2320-2327--Sreenivasulu Megati et al. "Unsaturated phosphonates as acyclic nucleotide analogues. Anomalous Michaelis-Arbuzov and Michaelis-Becker reactions with multiple bond". J. Med. Chem. (1993) vol. 36, No. 10, pp. 1343-1355--M.R. Harden et al. "Novel acyclonucleotides: synthesis and antiviral activity of alkenylphosphonic acid derivatives of purines and a pyrimidine".
Patent History
Patent number: 5817647
Type: Grant
Filed: Nov 17, 1995
Date of Patent: Oct 6, 1998
Assignee: Merrell Pharmaceuticals Inc. (Cincinnati, OH)
Inventors: Patrick Casara (Ittenheim), Jean-Fran.cedilla.ois Nave (Strasbourg), Serge Halazy (Lagarrigue)
Primary Examiner: Mukund J. Shah
Assistant Examiner: Pavanaram K. Sripada
Attorney: Mark C. Nelligan
Application Number: 8/505,168